The long term objectives are to develop a novel treatment for human lupus that has fewer side effects than currently available immunosuppressive treatment and has improved efficacy. To this end, we have used a pre-clinical model of lupus and demonstrated that immunomodulation, i.e. skewing of the immune response away from antibody production and enhancing cell mediated immunity to include cytotoxic T lymphocytes is both feasible and beneficial in this model. The current proposal also demonstrates that lupus predisposition may relate to a pre-existing defect in interleukin-2 which promotes immune skewing. Using in vivo and vitro approaches combined with flow cytometry, genetic analysis and cellular immunology, this proposal has the following aims: 1) use pre-clinical models to determine whether defective T cell production of IL-2 predisposes to lupus, the mechanism by which this occurs, whether IL-2 replacement will be beneficial and adapt the murine approach to screen human lupus patients for similar abnormalities; 2) develop non IL-2 based immunomodulatory approaches (e.g., TLR stimulants) and test their efficacy in several murine models; 3) define the mechanism(s) that mediate sex differences in lupus severity in a murine model. These studies will provide novel insights into the role of IL-2 in lupus pathogenesis and identify new, non-immunosuppressive therapeutic approaches to lupus treatment.